Aza-benzimidazoles and process for their production

ABSTRACT

THERE ARE PRODUCED 4-AZA-BENZIMIDAZOLES OF THE FORMULA   1-R3,2-Y,5-R1,7-R2-1H-IMIDAZO(4,5-B)PYRIDINE   WHERE R1 IS FLUORINE, CHLORINE OR BROMINE R2 IS HYDROGEN OR 1-6 CARBON ALKYL R3 IS HYDROGEN, ALKYL OF 1-6 CARBON ATOMS, ALKYL OF 1-6 CARBON ATOMS HAVING A PHENYL SUBSTITUET OR CH2COX WHERE X IS AMINO, ALKLAMINO HAVING 1-6 CARBON ATOMS, HYDROXY OR ALKOXY OF 1-6 CARBON ATOMS, Y IS A HALOGEN, HYDROXY, MERCAPTO, AMINO, ALKOXY OF 1-6 CARBON ATOMS, BETA-HYDROXYETHYLAMINO, PHENYLALKYLAMINO IN WHICH THE ALKYL HAS 1-6 CARBON ATOMS, ALKLMERCAPTO OF 1-6 CARBON ATOMS, ALKYLAMINO WITH 1-6 CARBON ATOMS, PHENYL AMINO PYNDYLAMINO, ALKYL WITH 1-6 CARBON ATOMS, HYDROXYALKYL WITH 1-6 CARBON ATOMS, TRIFLUOROMETHYL,PHENYLALKYL HAVING 1-6 CARBON ATOMS IN THE ALKYL OR -SCH2COX AND PHARMACOLOGICALLY ACCEPTABLE SALTS THEREOF.

Uniwd O1 AZA-liENZIll/llDAZOLES-AND PROCESS FOR THEIRPRODUCIION Walter von Bebenhu'rg, jBuchschlag, Germany, assignor to Deutsche' 'Goldand Silber-Scheideanstalt vormals Roessler,Frankfnrt am Main, Germany I No Drawing; Filed Aug. -7, 1-972, Ser. No. 278,370

; 1. u:.'--Int. C]. C07d 31/50 US. Cl. 260.:-294.8 .C :1 Y 16 Claims ABsTRncT oF DISCLOSURE There are produced, 4-ana-benaimidagoles of the forceptable salts qt, a

v The I invention is *concerned with 4-aZa-benzimidazoles of the'formul'a whefe Rf is -fluorineg chlorine or bromine (i e., halogen of atomic weight 9 to '80),R is? hydrogen or 1-6 carbon alkyl; R is hydrogenfalkyl of 1 :6 carbon atoms, alkyl of 1 6 carbonatomsjhaving*"-aphenyl substituent or CHQCOX where 'Xis amino," alkylamino having 1-6 carbo' atoms, hydroicy or alkoxy' of 1'6-carb'on' atoms, Y i, lager; hydrox 'rner'captofamino, alkoxy of 1-6 carbo atoms, beta hydfoxyethylamirio, phenylalkylamino ih-which th'c alkyl ha's 1-6 carbonatom's, 'alkyl mercapto of l e-earbbnaroms; alkylaminor'with 1- 6 carbon atoms; pheiiylaimirio; pyridylamino, alkyl with 1-6 carbon atoms;

hydroxyalkyl l1" #6 carbon atoms, "'trifiuo'romethyl, pheny y p 6 carbonatoms in .thei'alkyl or -SGHgCOX d pharmacologically" acceptable salts mpounds' I are lice 4-aza-S-chlorobenzimidazolyl-.( 2 -mercaptoacetic acid, 2-benzylamino-4-aza-S-chlorobenzimidazole, 2-anilino-4aza-S-chlorobenzimidazole, Z-hydroxyethylamino-4-azo-S-chlorobenzimidazole, 1-benZyl-2-hydroXy-4 aza-5-chlorobenzimidazole, 4-aza-5-fiuorobenzimidazole, 2-isopropyl-4-aza-5-chloro-7-sec.-butyl-benzimidaz0le, 4-aza-5-bromo-7-hexyl-benzimidazole, 4-aza-5-fluoro7-ethyl-benzimidazole, 1-hexyl-4-aza-S-chlorobenzimidazole, 4-aza-S-chlorobenzimidazolyl-( 1 )-acetamide, 2-hydroxy-4-aza-S-chlorobenzimidazolyl-( 1 -methy1- acetamide, 4-aza-5-fiuorobenzimidazolyl-( 1 )-hexy1aceta1nide, 2-hydroxy-4-aza-5-chlorobenzimidazolyl- 1 -methy acetate, 4-aza-5-chlorobenzimidazolyl- (l )-hexyl acetate, 2-chloro-4-aza-5-chlorobenzimidazole, 2-fluoro-4-aza-5-chlorobenzimidazole, 2-bromo-4-aza-S-chlorobenzimidazole, 2-iodo-4-aza-S-bromobenzimidazole, Z-methoxy-4-aza-5-chloro-7-propyl-benzimidazole, 2-ethoXy-4-aza-S-chlorobenzimidazole, 2-hexoxy-4-aza-5-chlorobenzimidazole, 2-phenethylamino-4-aza-S-chlorobenzimidazole, 2-hexylmercapto-4-aza-5-chlorobenzimidazole, 2-amino-4-aza-5-bromobenzimidazole, Z-methylamino-4-aza-5-chlorobenzimidazole, Z-t-butylamino-4 aza-S-chlorobenzimidazole, 2-heXylamino-4-aza-5-chloro-7-methylbenzimidazole, 2-ethyl-4-aza-S-chlorobenzimidazole, 2-propyl-4-aza-5-fluoro-7-ethylbenzimidazole, 2-hexyl-4-aza-5-chlorobenzimidazo1e, 2-pyridylamino-4-aza-5-ch1orobenzimidazolc, 2-hydroxymethyl-4-aza-S-chlorobenzirnidazole, 2-hydroxyethyl-4-aza-5-chlorobenzimidazole, 2-hydroxyheXyl-4-aza-5-chlorobenZimidazole-2-benzyl- 4-aza-S-brornobenzimidazole, 4-aza-5-chlorobenzimidazolyl- (2 -mercaptoacetamide, 4-aza-S-chlorobenzimidazolyl- (2) -methyl mercaptoacetamide, 4-aza-S-chlorobenzimidazolyl- (2 -methyl mercaptoacetate, 4-aza-S-chloro-bcnzimidazolyl- (2) -hexyl mercaptoacetate, 1-ethyl-2-hydroxy-4-aza-S-chlorobenzimidazole, 1-propyl-2-mercapto-4-aza-S-chlorobenzimidazole.

The compounds of the invention have valuable pharmacological properties. They are especially noted for their good antiphlogistic activity as well as partially also their antiischemic activity. Especially favorable activity is shown for example in compounds where R is chlorine, R is hydrogen and R is either hydrogen or alkyl with 1 to 6- carbon atoms, especially 1 to 3 carbon atoms in the group CH COX while Y is either hydroxy, mercapto atoms or is trifiuoromethyl. v p H r Compoundsof the'invention can beip'repared' by either (a) Reacting a compound having, formula 1 except that R is hydroxy or etherified hydroxy, e .g alkogry, or amino (rather than halogen) witha halogenating agent or (b) Condensing to an .imidazole ring a compound having the formula v v ralkyl with 1 to 6 carbon atoms especially 1 to 4 carbon where R R and R are as defined in formula I and V is an amino group, a hydroxy group, are etherified hydroxy group, e.g., alkoxy, or a halogen with a compound having the formula YCN or a compound having the formula Y Y C=Z where Y is as defined in formula I, Z is oxygen, sulfur or defined as for Y or Y, and Y; together can mean sulfur.

Thus examples of compounds within formula II are 2-chloro 5,6 diaminopyridine, 2-bromo-5-amino-6-hydroxypyridine, 2-fluoro-5,6-diaminopyridine, 2-chloro-4- methyl-S-methylamino-6-aminopyridine, 2-bromo-5-hexylamino-S-amino 6 methoxypyridine, 2-chloro-4-hexyl-5- benzylamino-6-hydroxypyridine, 2-chloro-5-amino-6-chloropyridine, 2-chloro-5-amino-6-bromopyridine, Z-chloro- S-carboxymethylamino-fi-aminopyridine.

Representative compounds having the formula YCN are cyanogenchloride, cyanogen bromide, hydrogen cyanide, cyanamide, cyanic acid, thiocyanic acid. Representative compounds having the formula Y Y O=Z are carbon dioxide, carbon disulfide, carbon oxysulfide, urea, thiourea, guanidine, methyl chloroformate, ethyl chloroformates, hexylchloroformate, phenylchloroformate, methyl bromoformate, diethyl carbonate, B,B'-dihydr0xyethyl urea, sym.dibenzyl urea, dimethyl dithio carbonate, diethyl trithiocarbonate.

The compounds of the present invention whether prepared by process (a) or process (b) or by other process can be converted into their salts, preferably their salts of pharmacologically acceptable acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, maleic acid, fumaric acid, citric acid, lactic acid and p-toluenesulfonic acid.

As stated above according to process (a) there can be used a starting material of formula I where in place of the halogen R is an etherified hydroxy group. Such etherified hydroxy groups are preferably alkoxy groups, for example, having 1 to 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy and hexoxy or phenoxy. Thus there can be used 2-benzyl-4-aza-S-ethoxybenzimidazole, 2-mercapto-4-aza-5-hexoxybenzimidazole, 2-trifiuoromethyl-4-aza-S-phenoxy-benzimidazole.

In carrying out process (a) there is employed for example an elevated temperature, e.g. 50-200" C. with a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxybromide, thionyl chloride, thionyl bromide, etc., in a given case with the addition of an inert solvent. As inert solvents there can be used aromatic hydrocarbons such as benzene, toluene, etc. Frequently it is convenient to use an excess of the halogenation agent as the solvent.

In the case of process (a) where the R is replaced by an amino group in the starting material the action of the halogenation agent preferably takes place in combination with a diazolization (Sandmeyer reaction or modified Sandmeyer process) in the presence of the corresponding halide ion and/or the corresponding copper (I) salt or the fluoroborate ion. It is likewise possible to isolate the intermediate product of the Sandmeyer reaction and to decompose it thermally.

. Process (b) can be carried out with or without solvents in a temperature range of 0.300 C., for example. As solvents there can be used polar compound, for example water, alcohols, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol and butyl alcohol, dimethyl form-v amide, dimethyl sulfonate, dioxane, polyphosphoric acid, etc. Likewise there can be used an excess of the component Y Y C=Z as the solvent in the event this material is a liquid. In a given case there can be added in process (b) basic compounds such as, for example, alkali hydroxides, e.g., sodium hydroxide and potassium hydroxide, alcoholates, e.g., sodium methylate, potassium methylate, sodium ethylate and potassium ethylate. The use of these alkaline materials is particularly desirable when one reaction component is carbon disulfide.

As starting materials having the formula YCN there are especially used compounds where Y is a halogen atom; an amino group, a hydroxy group or a mercapto group.

Process (b) can also be carried out in such a manner that an intermediate product in which the amino group in either the 2 or 3 position of the pyridine ring is substituted by the group 'CY=Z.is isolated.'This intermediate compound is then cyclized with the splitting off .for example of water, alcohol,.ammonia or an amine. This procedure can be carried out forexample with or without a solvent at a temperature between 50-and300 C. In case a solvent is used those mentioned above can be employed. In a given case there can be added the customary condensation reagents, for example polyphosphoric acid.

If V is an etherified hydroxy group it is preferably lower alkoxy, e.g., methoxy to hexoxy, or phenoxy. In compounds of formula I wherein Y means a halogen atom or a hydroxy, mercapto, amino, alkylmercapto, alkoxy or alkylamino group these groups can be substituted for each other or a dilferent one of the above set forth group Y. This reaction can be carried out with or without solvent at a temperature in the range of 50-250 C. for example. As solvents there can be used for example the polar solvent set forth above, e.g., water, alcohols, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, dimethyl formamide, dimethyl sulfoxide, etc.' Frequently it is expedient to add acid binding agents such as, for example, soda lye, potassium hydroxide, tertiary amines, e.g., trimethylamine, triethylamine, pyri dine, alkali carbonates, e.g.,sodium carbonate and potassium carbonate, etc. v I

In the event that Y is a hydroxy group, a mercapto group or an amine group this reaction process (-b) can be carried out for example by alkylation using the customary alkylation agents such as lower alkyl halides, e.g., methyl chloride, ethyl chlorid'e,fl hexyl chloride, isopropyl chloride, butyl chloride, methyl bromide, phenylalkyl halides, e.g., benzylchloride and benzyl bromide, haloacetic acid, e.g., chloroacetic acid, bromoacetic acid, iodoacetic acid, alkyl haloacetates, e.g., methyl chloroacetate, methyl bromoacetate and ethyl chloroacetate, haloacetamides, e.g., chloroacetamide and bromoacetamide or by means of the corresponding sulfonic acid esters such as dialkyl sulfates, e.g., dimethyl sulfate or diethyl sulfate, dimethyl sulfoxide, aliphatic arylsulfonic acid alkyl esters, e.g., methyl p-toluenesulfonate and ethyl p-toluenesulfonate, arylsulfonic acid phenyl and benzyl esters, e.g., phenyl p-toluenesulfonate, benzyl p-toluenesulfonate and phenyl benzenesulfonate (see, for example, Fieser and Fieser Reagents for Organic Synthesis, Vol. 1 (1967) pages 1303-4 and Vol. 2 (1969),-page 471, John Wiley and Sons, Inc., New York for other suitable alkylating agents).

In the event Y is a halogen or an alkoxy or alkyl group or an amino or alkylamino group process (b) can 'be carried out by reacting the compound of formula II with a compound supplying the corresponding .Y group, e.g., an amine, e.g., propyl amine, or alcohol, e.g., ethyl alcohol, mercaptoderivative or a base,-for. example, sodium sulfide orpotassium-sulfide, alkali hydroxide, e.g.,

sodium hydroxide or potassium hydroxide, lower alkyl mercaptans, e.g., methyl mercaptane, ethyl mercaptan, t-

butyl mercaptan, hexyl mercaptan, lower aliphatic alco mercaptoacetic acid, alkyl 'mercaptoacetates, e.-g.,'methyl mercaptoacetate, ethyl mercaptoacetate, isooctyl mercaptoacetate, mercaptoacetamide, mercapto alkyl acetarnides,

e.g., mercapto methyl, acetamide or the customary halo-' genating agents such as those set forthabove for example. Furthermore compounds of formula I in WhichR is hydrogen can be converted to compounds in which R' is alkyl, in a given case substituted by a phenyl group or the group CH OOX if this is reacted with the compound of formula I a lower alkyl halide, e.g., methyl chloride, methyl bromide, ethyl chloride, propylchloride or a phenyl substituted lower alkyl halide, e.g., benzyl halides such as benzyl chloride and benzyl bromide, or a lower alkyl haloacetate, e.g., methyl chloroacetate, ethyl chloroacetate, propyl bromoacetate, or a haloacetamide, e.g., chloroacetamide or bromoacetamide, a haloacetic acid, e.g., chloroacetic acid or bromoacetic acid, or a dialkyl sulfate, e.g., dimethyl sulfate or diethyl sulfate or in a given case in regard to the ester group by a phenyl substituted arylsulfonic acid alkyl ester. This reaction is suitably carried out in inert solvents such as dimethylsulfoxide, toluene, dioxane, etc. with or without the addition of acid binding reagents such as alkate carbonates, e.g., sodium carbonate or potassium carbonate, alkali amides, e.g., sodamide, potassium amide, alkali hydrides, e.g., sodium hydride, lithium hydride, etc. at a temperature, for example, within the range of 20 to 150 C.

With compounds that contain the -COX group, in the case where X is an amino group, an alkylamino group or an alkoxy group these can be saponified to a hydroxy group, or in case X is a hydroxy group or an alkoxy group it can be converted with a corresponding alkanol having 1 to 6 carbon atoms to an alkoxy group or (when X already is alkoxy) to a difierent alkoxy group, or by reaction with ammonia or an alkyl amine of 1 to 6 carbon atoms the hydroxy or alkoxy group can be amidated.

When a compound of formula I in which R is hydrogen is reacted in the manner set forth above isomeric mixtures can be formed in which the radical R is on the nitrogen atom in the 3-position of the benzimidazole ring. The desired isomer corresponding to formula I in this case is separated oif by fractional crystallization or other customary processes, as for example a chromatographic process (column chromatography) or extraction.

Basic compounds of formula I, as for example 2-benzylamino-4-azo-S-chlorobenzimidazole can be converted to salts by known procedures. As anions for these salts there can be used known and therapeutically usable acid radicals, such as those set forth previously for example.

Compounds of formula I of an acid character, as for example 2 hydroxy-4-aza-5-chlorobenzimidazolyl-(1)- acetic acid can be converted in the customary manner into their alkali, e.g., sodium or potassium, ammonium or substituted ammonium salts. As substituted ammonium salts there may be noted especially salts of tertiary alkyl amines, e.g., trimethylamine, triethylamine, tributylamine and ethyl dipropylamine, lower aminoalcohols, e.g., ethanolamine and propanolamine, as well as bis and tris (hydroxyalkyl) amines (alkyl radicals having 1 to 6 carbon atoms), e.g., diethanolamine, dipropanolamine, dihexanolamine, triethanolamine and tripropanolamine.

Each compound of formula I which contains asymmetrical carbon atoms and as a rule occurs as the racemate can be split into the optically active isomers in known manner, for example by means of an optically active acid. However, it is also possible from the start to employ an optically active or disastereomeric starting material in which case the final product will have a correspondingly optically active form or disastereomer configuration.

In case the symbol R is hydrogen the compounds of formula I within the invention are tautomeric with compound in which the hydrogen is not on the nitrogen atom in the 1 position of the benzimidazole ring but is on the nitrogen atom in the 3 position of the benzimidazole. The compounds of formula I in this case can be present entirely or partially in both possible tautomeric forms. Generally under normal operating and storage conditions they are present in equilibrium.

PRODUCTION OF THE STARTING MATERIAL For Process (a) 2-amino-3-nitro-6-chloropyridine ,is reacted in a polar solvent such as a lower alkanol, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol, propyl alcohol or butyl alcohol with ammonia, alkali alcoholates, e.g., sodium methylate, potassium methylate or sodium ethylate, or alkali; e.g., sodium hydroxide or potassium hydroxide, in a given case with an excess of the basic component or in a given case in the presence of a tertiary amine, e.g., trimethylamine, triethylamine, tributylamine or dimethyl aniline as hydrochloric acid acceptors at a temperature between 0 and 200 C. In the compounds obtained the nitro group is reduced to an amino group by hydrogenation in the presence of Raney-nickel or noble metal hydrogenation catalysts such as palladium or platinum, suitably at a temperature between 20 and C. in a solvent such as an alcohol, e.g., methyl alcohol, ethyl alcohol or butyl alcohol, dioxane, or tetrahydrofurane and the thus obtained compound is converted to the corresponding imidazole derivative by process (b). The following example illustrates this process.

To a solution of 10 grams of sodium in 400 ml. of ethanol there were added at room temperature 50 grams of 2-amino-3-nitro-6-chloropyridine in portions. After the end of the addition heating at reflux with stirring for a further 30 minutes. In the cooling off the reaction product crystallized. It was filtered off with suction and washed with much water and alcohol. Yield 35 grams.

The 2-amino-3-nitro-6-ethoxypyridine was then hydrogenated in 500 ml. of dioxane'with addition of 10 grams of Raney-nickel and 20 grams of MgSO at 50 atmospheres excess pressure and 40-50" C. The reaction solution was sucked off over a filter bed, and the filtrate treated with 25 ml. of ethyl chloroformate with stirring. After a short time the 2 amino 3 carbethoxyamino- 6-ethoxypyridine crystallized out which was directly further reacted after filtering with suction and washing. The carbethoxy compound was heated in a round bottomed flask at 220-240 C. for 2 hours with occasional stirring whereupon it began to sinter and ethanol to split off. The residue was recrystallized from dimethyl formamide (DMF) after cooling. There were obtained 15 grams of 2 hydroxy-4-aza-S-ethoxy-benzimidazole M.P. 300 C.

To a solution of 62 grams 2,3,6-triaminopyridine in dioxane 60 grams of ethylchloroformate are added with stirring. The precipitating 2,6-diamino-3-carboethoxyaminopyridinehydrochloride is filtered off and dried. This compound is heated for 2 hours to ZOO-220 C. The resulting 2-hydroxy-4-aza'5-aminobenzimidazole.HCl can be recrystallized from methanol. Yield 34 grams; M.P. 258-262 C. From the warm aqueous solution the base can be precipitated by addition of dilute NaOH. M.P. 300 C.

PRODUCTION OF STARTING MATERIAL For Process (b) A 2,6-dihalogen-3-nitropyridine, e.g., 2,6-dichloro-3- nitropyridine or a Z-amino-6-halogen-3-nitropyridine, e.g., 2-amino-6-chloro-3-nitropyridine was reduced to the 3- amino-pyridine derivative in the presence of Raneynickel or a noble metal hydrogenation catalyst such as palladium or platinum in a polar solvent such as an alcohol, e.g., ethyl alcohol, methyl alcohol or butyl alcohol, dioxane, tetrahydrofurane, etc. at a temperature between 20 and 150 C., in a given case with pressure. For the production of such compounds in which V of formula II is a hydroxy group or an etherified hydroxy group, for example 2,6-dichloro-3-nitropyridine is reacted with an equivalent alcoholate, e.g., sodium ethylate or potassium methylate or alkali phenolate, e.g., sodium phenolate or potassium phenolate, or an equivalent alkali, e.g., sodium hydroxide or potassium hydroxide, in a given case in the presence of a tertiary amine, e.g., trimethylamine, triethyl amine, tributyl amine or dimethyl aniline in a polar solvent at .a temperature between -50 and +l C., preferably between 50 and C. and the nitro group of the compound obtained is reduced to an amino group by hydrogenation in the presence of Raneynickel or a noble metal catalyst such as palladium or platinum, for example at a temperature between 20 and 150 C. in a solvent such as an alcohol, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol or butyl alcohol, dioxane or tetrahydrofurane.

In the thus obtained compounds the R radical can be introduced as follows:

The pyridine derivative can be reacted with an aliphatic carboxylic acid halide having 1 to 6 carbon atoms, e.g., an alkanoic acid halide such as formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeroyl chloride, caproyl chloride or acetyl bromide. The acyl halide can have a phenyl radical attached, e.g., phenyl acetyl chloride. In the reaction the amino group in the 3 position is acrylated and subsequently the CO group reduced to the CH group with lithium aluminum hydride or reacted with a compound of the formula HalCH COX (Hal is chloride or bromine);

or the pyridine derivative is reacted with an aliphatic aldehyde with 1 to 6 carbon atoms, e.g., formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, or caproaldehyde, or an aliphatic aldehyde having a phenyl radical attached, e.g., phenylacetaldehyde or an aldehyde of the formula OHC-COX, in a polar solvent (for example alcohols, e.g., ethyl alcohol) for example at 0 to 50 C. and the Schiff base obtained catalytically reduced in the presence of Raney-nickel or noble metal catalysts or sodium borohydride. The process is illustrated by the following example:

50 grams of 2-amino-3-nitro-6-chloropyridine in 500 ml. of dioxane after the addition of 20 grams of MgSO and 10 grams of Raney-nickel were reduced at 30-40 atmospheres excess pressure and 30-40 C. The hydrogenated solution was filtered and treated with 100 ml. of 6-normal isopropanolic HCl with stirring, whereupon 2,3-diamino-6-chloropyridine, hyldrochloride precipitated. It can be recrystallized from ethanol. The compound is very sensitive to air. Yield 40 grams; M.P. 3 00 C.

To the solution in dioxane of 2,3-diamino-6-chloropyridine produced above (40 grams in 500 ml. of dioxane) there were added dropwise with stirring 30 ml. of ethyl chloroformate. The 2-amino-3-carbethoxyamino- 6-chloropyridine hydrochloride soon crystallized out. The compound can be recrystallized from ethanol. Yield 55 grams; M.P. 190-2 C.

50 grams of 2-amino-3-nitro-6-chloropyridine in 450 ml. of ethanol were hydrogenated after the addition of 20 grams of Raney-nickel at 20-40 C. and 50 atmospheres excess pressure, the solution filtrated and 32 ml. of benzaldehyde added. The Schifis base which crystallized out was filtered off with suction and recrystallized from acetone. Yield 42 grams; M.P. 180-182 C.

28 grams of the Schifis base were treated in a mixture of 500 ml. of dioxane and 500 ml. of methanol with 20 grams of sodium borohydride in portions. The temperature of the stirred mixture was held at 30-35" C. After 3 hours there were added 150 ml. of 6 normal isopropanolic HCl and evaporated to dryness. The residue was dissolved in methanol, alkalized with aqueous NaOH and the crystallized 2-amino-3-benzylamino-6-chloropyridine filtered off with suction. Yield 28 grams; M.P. l40-l42 C.

2-Methoxy-3-nitro-6-chloropyridine To a solution of 19.3 grams (0.1 mole) of 2,6-dichloro- 3-nitro-pyridine in 200 ml. methanol there were added with stirring in portions 13.8 grams (0.1 mole) of powdered potash. An exothermic reaction resulted; the temperature was held at 10 to C. by cooling. The

mixture was stirred for 2 hours. The dissolved material can be directly reduced on the nitro group.

2 hydroxy 3 nitro 6 chloropyridine, for example can also be produced by heating 2-amino-3-nitro-6- chloropyridine with nitrous acid.

The compounds of the invention are suited for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain as the active material one or several of the compounds of the invention, in a given case in admixture with other pharmacologically or pharmaceutically effective materials. The production of the medicine can take place with the use of known and customary pharmaceutical carriers and diluents, as well as other customary assistants.

Such carriers and assistants are set forth for example in Ullmanns Encyklopadie der technischer Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 et seq: Hiv. Czetsch- Lindenwald, Hilfstoffe fur Pharmazie und angrenzende Ge'biete; as well as in Pharm. 2nd. Vol. 2 (1961), pages 72 et seq.

Examples of such materials include gelatin, sucrose, pectin, starch, tylose, talc, lycopodium, silica, lactose, cellulose derivatives, micropulverized cellulose, stearates, e.g., methylstearate and glyceryl stearate, emulsifiers, vegetable oils, water, pharmaceutically compatible monoor polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, as well as derivatives of such alcohols and polyglycols, dimethyl sulfoxide, esters of saturated and unsaturated fatty acids with monoor polyvalent alcohols such as glycols, glycerine, diethylene'glycol, perthaerythritol, sorbitol, mannitol, etc., e.g., glyceryl stearate, glyceryl palmitate, glyceryl oleate, ethylene glycol stearate; such esters of polyvalent alcohols can in a given case also be etherified, benzyl benzoate, dioxolano, glycerine formul, glycol furfural, dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate, ethyl carbonate, etc.

Furthermore there can be added preservatives, stabilizers, buffers, taste correctives, antioxidants and complex formers (for example ethylenediaminotetraacetic acid) and the like. In a given case for stabilization of the active molecule a pH in the range of about 6-8 can be established with physiologically compatible acids or buffers.

As antioxidants there can be used for example sodium meta bisulfite and ascorbic acid, as preservatives there can be used for example sorbic acid, p-hydroxybenzoic acid esters, e.g., methyl p-hydroxybenzoate and ethyl phydroxybenzoate and similar materials.

The pharmacological and galenical treatment of the compounds of the invention takes place according to the usual standard methods.

The drugs can be used enterally parenterally, orally, perlingually or in the form of sprays.

The addition of other medicinally active materials is also desirable, especially the addition of analgesically and antiphlogistically effective substances.

The compounds of the invention have a good antiphlogistic and antiischemic activity.

The antiphlogistic activity is comparable to that of the known drug salicylamide.

The lowest effective antiphlogistic dosages in animal experiments for example are 20 mg./ kg. body weight-orally 10 mg./ kg. body weight-sublingually 5 mg./ kg. body weightintravenously As a general range of dosage for activity (based on animal studies) there can be employed 20-200 mg./kg. body weight-orally 10-100 mg./kg. body weightsublingually 5-20 mg./kg. body weightintravenously The compounds of the invention have utility in treating rheumatic fever, chronicqheumatic, arthritis, Morbus Bechterew, spondylosis, arthrosis, discopathy, gout, fibrosis, periarthritis, neuritis,. neuralgia, surface thrombophlebitis, angina pectoris and coronary blood flow disturbances. v

The addition of other medicinally active material is also favorable, especially analgesically and 'antiphlogistically effective substances. 7 I i The pharmaceutical preparations generally contain between 1 and 50 weight percent of the active component of the invention. U l

The compounds can be delivered in the-form of tablets, capsules, pills, dragees, suppositories, gels, cremes, powders, liquids, dusts or aerosols. As liquids there can be used oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions. The preferred forms of use are tablets which contain between 50 and 200 mg.of active material as solutions which contain between 0.5 and 2% of active material.

In individual doses the amount of active component of the invention can be used for example in an amount of 200 mg. dispensed orally or mg. dispensed intravenously in each case calculated as the free base. These doses can be dispensed once or several times a day.

For example there is recommended the use of 1 to 9 tablets containing 200 mw. of active ingredient 3 times daiIy or intravenously the injection 1 to 3 times a day of a ml. ampoule having 10 mg. of active material.

The acute toxicity of, the compounds of the invention in the mouse (expressed by the LD 50 mg./kg. method of Miller 'a'ndiTainter, Proc. Soc. Exph. Biol. and Med., Vol. 57 (1944),. pages 261 et seq.) in oral application is at least 500 mg./kg. for example 8000 mg./kg. in some cases.

The drugs can be, used in human medicine, in veterinary medicine, e.g., to treat cats, dogs, horses, sheep, cattle, goats and pigs or in agriculture. The drugs can be used alone or in admixture with other pharm'acologically active materials.

Unless otherwise indicated, all parts. and percentages are by weight; a

EXAMPLE 1 2-Methyl-4-aza-S-chlorobenzimidazole I 65 grams of 2-amino-3-acetylamino-6-chloropyridine were heated at l80-200 C. for 45 minutes. The compound became solid during the heating. The product was recrystallized from methanol. Yield 35 grams; M.P. 254- 256 C. 1

/ .2 -Benyzl-4 -az a-S-chlorobenzimidazole Yield 16, ram -,MP. 215 21790.-.

50 grams of 2,3-diamino-6-chloropyridine and 40 grams of trifluoro acid were dissolved in 250 ml. of ethyl alcohol and heated on the water bath for 15 minutes. Then the alcohol was distilled olf and the residue heated for 1 hour at -210 C. Upon cooling the melt crystallized. For purification purposes the compound was recrystallized twice from methanol employing carbon for clarification. Yield 13 grams; M.P. 228230 C.

EXAMPLE 4 2-Mercapto-4-aza-5-chlorobenzimidazole 50 grams of 2,3-diamino-6-chloropyridine were dissolved in 500 ml. of ethyl alcohol. The solution was treated with 50 ml. of carbon disulfide and 15 ml. of 40% sodium hydroxide and heated under reflux for 4 hours. The solution was acidified with hydrochloric acid and the alchol distilled oil. The residue was stirred with water. The crystals were sucked OE and then washed with water. The crystals were dissolved in warm sodium carbonate solution, clarified with carbon and the solution filtered. The filtrate was acidified with hydrochloric acid whereupon the compound again crystallized out. Yield 35 grams; M.P. 7300 C.

EXAMPLE 5 2-Hydroxy-4-aza-5-chlorobenzimidazole 84 grams of 2-amino-3-carbethoxy-amino-4-chloro-pyridine were heated at 189-200 C. for 1 hour. The product was purified by recrystallization from dimethyl formamide. Yield 40 grams; M.P. 300 C.

EXAMPLE 6 2-Hydroxy-4-aza-S-bromo-7-methyl benzimidazole ITN 1 1 EXAMPLE 7 2-Hydroxy-4-aza-S-chlorobenzimidazolyl-( 1 acetic acid cm-C 0H 1'.

34 grams of 2 hydroxy-4-aza-S-chlorobenizimidazole were dissolved in 400 ml. of dimethyl formamide. There were then added in portions at 2025 C. 9.6 grams of NaH (55% The mixture was stirred for 30 minutes at 20 C. Then they were dropped in 26 ml. of ethyl chloroformate, whereupon the temperature increased to 35 C. The mixture was stirred for 3 hours longer at 6070 C. Then the solution was poured into 3 liters of water, whereupon the product crystallized. It was sucked off and washed with water. The ester thus obtained was heated for 1 hour under reflux with a solution of 21 grams of potassium hydroxide in 200 ml. of water and 600 ml. of ethyl alcohol. Then the solution Was acidified with hydrochloric acid and evaporated to dryness. The residue was dissolved in dilute soda solution. The insoluble starting mateiral was filtered off. The filtrate was acidified with hydrochloric acid, whereupon the acid product crystallized. It was recrystallized from water. Yield 7 grams; M.P. 213215 C.

EXAMPLE 8 2-Methyl-4-aza-S-chlorobenzimidazolyl-( 1 )-acetic acid GHQ-C 0 0H 65 grams of 2-methyl-4-aza-S-chlorobenzimidazole were dissolved in 800 ml. of dimethyl formamide. Then there was added in portions at 2025 C. 19.6 grams of NaH (55 The mixture was subsequently stirred for 30 minutes. Then there were dropped in 53 ml. of ethyl chloroformate, whereupon the temperature rose to 35 C. The mixture was stirred for an additional 3 hours at 35 C. The solution was cooled and treated with 50 ml. of water and 25 ml. of acetic acid. The solvent was distilled 011 in a vacuum. The residue was treated with water, whereupon the product crystallized. In this reaction 2 isomers were formed. The desired compound was obtained in pure form by recrystallizing twice from ethyl alcohol. The thus obtained ester was heated under reflux with a solution of 15 grams of potassium hydroxide in 50 ml. of water and 350 ml. of ethyl alcohol for 1 hour. Then the solution was acidified with hydrochloric acid and evaporated to dryness. The residue was stirred with water. The crystals were sucked off and subsequently washed with water. The product was then recrystallized from water. Yield 7 grams; M.P. 240-243 C.

EXAMPLE 9 1-Methyl-2-hydroxy-4-aza-5-chlorobenzimidazole whereupon the temperature rose to 40" C. The reaction mixture was allowed to stand overnight (16 hours) at room temperature. Then there were added 50 ml. of water and 25 ml. of glacial acetic acid. The'solve'nt was distilled off in a vacuum. The residue was treated with water, whereupon it crystallized. The crystals were sucked off and washed with water. Then they were dissolved in chloroform. The insoluble starting material was filtered off and the filtrate evaporated to dryness. There were obtained 37 grams of a mixture of isomers. The desired compound was separated from its isomers by-dry column chromatography (column filling silica gel; running agent; 94 vol. percent CHCl and 6 vol. 7% C H OH). There were obtained 14 grams of product which was recrystallized from ethylalcohol. Yield 10 grams; M.P. 182 C.

EXAMPLE 10 Z-Methylmercapto-4-aza-5-chlorobenzimidazole EXAMPLE 1 1 4-Aza-S-chlorobenzimidazolyl-(2)EmercaptOacetic acid 30 grams of 2-mercapto-4-aza-5-chlorobenzimidazole were heated with 14 grams of chloracetic acid and 12 grams of sodium hydroxide in 300 ml. of water for 3 hours at 70 C. The reaction mixture was allowed to stand overnight at room temperature. The solution was filtered and the filtrate acidified with acetic acid. Thereupon the product crystallized out. It was dissolved in dilute sodium bicarbonate solution. The solution was clarified with carbon and filtered. The filtrate was acidified with glacial acetic acid, whereupon the product again crystallized out. It was sucked off and post washed with water. Yield 7 grams; M.P. 218220 C.

EXAMPLE I 12 2-Benzylamino-4-aza-S-chlorobenzimidazole 13 EXAMPLE 13 30 grams of 2-methylmercapto-4-aza-S-chlorobenzimidazole were heated at 170-180 C. for 5 hours with 160 ml. aniline. The desired compound crystallized out in part during the reaction. The cold reaction mixture was stirred with ethyl alcohol, the crystals were sucked off and subsequently washed with alcohol. The product was recrystallized from dimethyl formamide. Yield 20 grams; M.P. 300 C.

EXAMPLE 14 Z-Hydroxyethylamino-4-aza-5-chlorobenzimidazole 30 grams of 2-methylmercapto-4-aza-S-chlorobenzimidazole were heated for 7 hours at 170180 C. with 160 grams of ethanolamine. Then the excess ethanolamine was distilled off in a vacuum. The residue was stirred with ethyl alcohol, whereupon it crystallized. The crystals were sucked off and subsequently washed with alcohol. They were recrystallized from n-propanol. Yield 13 grams; M.P. 236-238 C.

EXAMPLE 15 1-Benzyl-2-hydroxy-4 aza-S-chlorobenzimidazole GHQQ l:

CI N

EXAMPLE 16 Z-Hydroxy-4-aza-S-fluoro-benzimidazole To a solution of grams 2-hydroxy-4-aza-5-aminobenzimidazole in 30 ml. 40% aqueous hydrofluoride acid a solution of 10 grams sodiumnitrite in 20 ml. water is added in portions at 0-5 C. with stirring. The reaction product crystallizes from the reaction mixture within one hour. It is analytically pure. Yield 7 grams; M.P. 300 C.

What is claimed is: 1. A 4-aza-benzimidazole of the formula where R; is chlorine or bromine, R is hydrogen, straight chain 1-6 carbon alkyl, R is hydrogen, straight chain alkyl of 1-6 carbon atoms, benzyl or CH COOH, Y is hydroxy, mercapto, beta-hydroxyethyl-amino, benzylamino, straight chain alkyl mercapto of 16 carbon atoms, phenylamino, straight chain alkyl with 1-6 carbon atoms, benzyl or SCH COOH and pharmacologically acceptable salts thereof.

2. A compound according to claim 1 wherein R is chlorine and R is hydrogen.

3. A compound according to claim 2 wherein Y is hydroxy, mercapto, straight chain alkyl of 1 to 6 carbon atoms.

4. A compound according to claim 3 wherein R is hydrogen.

5. A compound according to claim 3 wherein R is straight chain alkyl of 1 to 6 carbon atoms.

6. A compound according to claim 5 wherein R is straight chain alkyl of 1 to 3 carbon atoms.

7. A compound according to claim 3 wherein R is -CHCOOH.

8. A compound according to claim 1 where R is chlorine, R is hydrogen or straight chain alkyl of 1-6 carbon atoms, R is hydrogen, straight chain alkyl of 1-6 carbon atoms or -CH COOH, Y is hydroxy, mercapto, straight chain alkyl with 1-6 carbon atoms or benzyl.

9. A compound according to claim 8 wherein any alkyl present has 1 to 2 carbon atoms.

10. A compound according to claim 9 wherein any alkyl is methyl.

11. A compound according to claim 1 which is 2-mercapto-4-aza-5-chlorobenzimidazole.

12. A compound according to claim 1 which is 2-methyl-4-aza-5-chlorobenzimidazole.

13. A compound according to claim 1 which is Z-benzyl- 4-aza-S-chlorobenzimidazole.

14. A compound according to claim 1 which is 2-hydroxy-4-aza-5-bromo-7-methyl benzimidazole.

15. A compound according to claim 1 which is Z-methyl-4-aza-5-chlorobenzimidazolyl-( 1 -acetic acid.

16. A compound according to claim 1 which is l-methyl-2-hydroxy-4-aza-5-chlorobenzimidazole.

References Cited UNITED STATES PATENTS 3,459,759 8/1969 Rochling et a1. 260-296 H 3,561,948 2/1971 Dealtry et al 7192 3,609,157 9/1971 Allan et a1 260---295 F OTHER REFERENCES Roberts et al.: Basic Principles of Organic Chemistry, Benjamin Publishers, p. 806, 1965.

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

260-295 F, 296 H, 296 R; 424-263, 266

- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. i ,6 lO i i I Dated June 25 197 4 Inventor(S) Walter vonBebenburg It is certified that error appears in the above-dden'tified patent and that said Letters Patent are 'hereby' corrected as shown below:

Column 1, insert Claims priority of Austrian Application 7 No. A/7A88/ 71 filed August 26, 1971 Sigried and sealed this 1st day of October 1974.

(SEAL) Attest: I '7 MCCOY M. GIBSON JR. c. MARSHALL DANN Attesting' Officer Commissioner of Patents 7 FORM po-mso (10-69) USCOMMQDC 00376 P U GOVIINIENY PIINIING O'Il cl l". 0-166-1) 

